JPH0328432B2 - - Google Patents

Abstract

The present invention refers to a new process for preparing N-2,3,4,5-substituted-1H-pyrrol-1-yl)-6-substituted amino-3-pyridazineamine, known as antihypertensive agents. The process is characterized in that a suitable 3,6-dihalogenopyridazine is reacted with hydrazine hydrate or other hydrazine derivatives of formula NH2 NHR, the obtained compound is reacted with a suitable dicarbonyl compound yielding first an alcandione-bis-[6-halogen-3-pyridazininyl]hydrazone, and then a 6-halogen-3-pyrrolylpyridazineamine derivative which is in turn reacted with an amine to yield the desired compounds.

Description

[Detailed description of the invention]

The present invention is based on the general formula [wherein the symbols R, R ¹ , R ² and R ³ may be the same or different and are independently selected from hydrogen and (C ₁ -C ₄ )alkyl, and R ⁴ is Hydrogen, ( _C1 - _C4 )alkyl, mono- or di-
( _C1 - _C4 )alkylamino-( _C1 - _C4 )alkyl,
Halogen (C ₁ - _{C 4} ) Alkanoyl, Carbo (C _1
-C4 ) alkoxy, carbobenzyloxy, ^R5 and ^R6 independently represent hydrogen, ( _C1 - _C6 ) alkyl, ( _C2 - _C6 ) alkenyl, ( _C3 - _C6 ) alkynyl , hydroxy-( _C1 - _C6 )alkyl, ( _C1 - _C4 )
represents alkoxy( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkanoyloxy( _C1 - _C6 )alkyl, phenyl or phenyl( _C1 - _C4 )alkyl, where the phenyl group is independently with 1 to 3 substituents selected from chloro, bromo, fluoro, ( _C1 - _C4 )alkyl, ( _C1 - _C4 )alkoxy, hydroxy and hydroxy ( _C1 - _C4 )alkyl, or methylene optionally substituted with a dioxy group, or R ⁵ and R ⁶ together with the adjacent nitrogen atoms represent a 5- to 7-membered heterocyclic ring that is fully or partially hydrogenated; may contain other heteroatoms selected from O, N and S and optionally ( _C1 - _C4 ) alkyl, hydroxy, hydroxy ( _C1 - _C4 ) alkyl, ( _C1 - _C4) ) alkoxy, optionally independently chloro, fluoro, bromo,
Hydroxy( _C1 - _C4 )alkyl and ( _C1 - _C4 )
It may have 1 or 2 substituents selected from phenyl, which may be substituted with 1 to 3 substituents selected from alkoxy, and R ⁷ and R ⁸
represents a hydrogen atom or taken together 1,3-
butadienylene group, which forms a benzo system fused with a pyridazine ring] and a novel method for producing their oxidized salts. In the method of the present invention described in the reaction formula, R ⁷ and R ⁸ are 3,6- as described above.
reacting a dihalogenopyridazine with a hydrazine hydrate or hydrazine derivative of the formula _NH2 - ^NHR4 ,
The compound of formula obtained is then reacted with an appropriately selected dicarbonyl compound of formula and finally the 6-halo-N-pyrrolyl-3-pyridazine amine obtained is reacted with an amine of formula NHR ⁵ R ⁶ It is a multi-step process consisting essentially of producing the desired compound of formula: N-pyrrolylpyridazineamine of the formula is known from European Patent Application Publication No. 9655 as an antihypertensive agent. According to the application, a compound of the formula comprises at least an equimolar amount of a 3-hydrazino-6-substituted aminopyridazine derivative of the formula

It is produced by reacting with a dicarbonyl compound of the formula: [wherein R, R ¹ , R ² and R ³ have the above meanings]. In the same application, the compound of formula
1157642, 1373548 and 1299421; Bellasio et al. Il FarmacoEd.Sci. 24 , 924
(1969) and Pifferi et al., Journal of
Medicinal Chemistry 18 , 741 (1975). These methods are summarized in Reaction Scheme 2 below. 3,6-dihalogenpyridazine derivatives of the formula [where R ⁷ and R ⁸ have the above meanings and halo
represents chloro, bromo or iodo] with twice the molar amount of a suitable amine of formula R ⁵ R ⁶ NH, in which R ⁵ and R ⁶ are as above, to produce a compound of formula do. The 3-halogen-6-pyridazine amine derivative thus obtained is then reacted with an excess of 98% hydrazine hydrate to produce the hydrazine derivative of formula. Following the reaction steps described in the above reaction scheme, a certain number of hydrazinepyridazine amines can be produced. however,
The reactivity towards nucleophilic substitution of halogen atoms in compounds of formula is reduced as the basicity of the R ⁵ R ⁶ N- group increases. As a result, the yield of the compound is reduced when the R ⁵ R ⁶ N- group is a strong electron donor, thus limiting the number of derivatives that can be conveniently prepared by these methods. Furthermore, when the above documents are taken together with Belgian patents 744286 and 744686 and German patent application 7009434, 6-hydrazino-
It is pointed out that experts dealing with the problem of synthesis of 3-pyridazine amines always prefer to add first the amine group and then the hydrazine group to the pyridazine ring. Some attempts made in our laboratory to reverse the order of addition of the reactants, i.e. to add the hydrazine group first and then the amine group, have shown that 3-halogen-6-pyridazine Ruhydrazine failed because it did not react with amines even at high pressures or temperatures. Furthermore, hydrazine derivatives of the formula are generally difficult to separate, so yields are often lower than expected, thus limiting the number of derivatives that can be conveniently prepared. The process of the present invention, which follows a novel step of adding hydrazine to the pyridazine ring before the addition of the amine group, provides compounds of formula give the compound. Furthermore, the method of the invention is more flexible and safer. In fact, the overall yield of N-pyrrolylpyridazine amine starting from 3,6-dihalogenpyridazine according to prior art methods is between 5% and 30% yield, whereas the overall yield according to the present invention is between 2% and 30%. It is more than double, and in both cases it is more than 30%. As mentioned above, another advantage is the increased flexibility of this method. Although in fact amino derivatives of various formulas R ⁵ R ⁶ NH can be easily used in the last reaction step irrespective of their basicity, ^{prior art} methods have (see above).
Another advantage is that the present method is safer than previously described methods because the first step of adding the hydrazine group to the pyridazine ring of the 3,6-dihalogenpyridazine requires a high concentration of hydrazine reactant. This is because it requires moderate concentrations of hydrazine hydrate (approximately 5-25%), well below the 40% value, which is believed to be the threshold at which the harm from using hydrazine hydrate begins to become significant. . on the other hand,
Prior art methods employ high concentrations of hydrazine hydrate (approximately
98%). Clearly, at this concentration, e.g. Merck Index 8th Edition 539
All the risks and disadvantages mentioned on the page are very large. As depicted in the reaction scheme, the first step of the process of the invention consists of the reaction of the selected 3,6-dihalogenpyridazine with hydrazine hydrate. As mentioned above, hydrazine hydrate is preferably 5
~25% hydrazine hydrate. This reaction step is carried out in the presence of a basic agent which acts as a hydrogen halide acceptor so as not to adversely affect the reactants or reaction products. According to a preferred embodiment, the basic reagent is used in equimolar amounts with the pyridazine derivative of formula or preferably in excess. Examples of such reagents are alkali metal or alkaline earth metal carbonates, bicarbonates and hydroxides. The reaction mixture is generally heated to a temperature between 60°C and reflux temperature, and preferably to reflux temperature.
Sometimes an organic solvent is added to help dissolve the reaction mixture, and then it is removed in vacuo before starting the reaction. The reaction time is generally 3 to 24 hours. Add water when the reaction is complete, and add half a molar amount or preferably a slight excess while keeping the temperature above 60 °C to save time and prevent precipitation of the halogenpyridazinylhydrazine of the formula. Add a dicarbonyl compound of the formula. After this addition, a compound of formula precipitates, which is collected and washed according to conventional procedures. To complete the precipitation, soak the solution in mineral acid, before collecting the precipitate.
Neutralization is preferably carried out with hydrohalic acid. To do this, 17% hydrochloric acid has been found to be particularly useful. In the second step of the process of the invention, an intermediate of the formula is reacted with a separate amount of a dicarbonyl compound,
A 6-halo-N-pyrrolyl-3-pyridazine amine of the formula is produced. The reaction is preferably carried out by adding intermediate V to a mixture of equimolar amounts of dicarbonyl compound and acid catalyst in a suitable organic solvent while heating to reflux temperature. Solvents that can be suitably used are, for example, lower alkanoic acids and their ( _C1 - _C4 ) alkyl esters, benzene, toluene, tetrahydrofuran, dioxane, etc., and mixtures thereof. Although several types of acidic catalysts can also be used, such as hydrohalic acids, sulfuric acid, p-toluenesulfonic acid and Lewis acids, lower alkanoic acids are particularly suitable since they can be used simultaneously as reaction solvent and catalyst. Among the lower alkanoic acids, acetic acid is preferred. Upon completion of the addition, an intermediate product of the formula precipitates, which is recovered by filtration;
and, if necessary, purified by conventional processes. On the other hand, depending on the solubility of the intermediate product of the formula in the solvent system used, the formation of the intermediate product 6-halo-3-hydrazino-pyridazine of the formula This is achieved in one step by directly adding an excess of the dicarbonyl compound of formula. Again, the resulting compound of formula is recovered by filtration and, if desired, purified in conventional manner. Finally, the equation 6-
The halo-N-pyrrolyl-3-pyridazine amine intermediate is prepared by the formula
Reaction of R ⁵ R ⁶ NH with an appropriately selected amine converts it to a compound of the desired formula. Particularly useful salts are hydrohalides such as hydrochloride,
Hydrobromide and hydrogen iodide salts. This reaction step is carried out using a suitable organic solvent, such as an alkanol having 3 to 6 carbon atoms, such as propanol, butanol, isobutanol, 1-pentanol, 2-pentanol, 3-pentanol, 3-methyl-2
- pentanol, 4-methyl-3-pentanol, 1-hexanol, 2-hexanol or 3-hexanol, cycloalkanols having 5 to 7 carbon atoms, such as cyclopentanol, cyclohexanol or cycloheptanol, 2 to 4 glycols and the corresponding mono- or di-( _C1 - _C2 ) alkyl ethers or esters, such as ethylene glycol, ethylene glycol monomethyl or monoethyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monoacetate, 1, 2-propanediol, 1,3-propanediol, 1,
3-propanediol monoacetate, 1,3-
Propanediol monoethyl ether, 1,2-
It can be carried out in the presence of butanediol, 2,3-butanediol, 2,3-butanediol monomethyl ether, benzyl alcohol. According to a preferred embodiment of the invention, in order to act as a reactant as well as a solvent in this reaction step,
A large excess of an appropriately selected amine of formula R ⁵ R ⁶ NH is used. In either case, the reaction mixture is heated to between about 85° C. and reflux temperature. Reaction times depend on the particular reactants and reaction conditions used, but the reaction is generally complete in about 2 to 12 hours. Next add water, keeping the temperature above 85°C. The separated solid is a derivative of formula, which is recovered by conventional methods. Sometimes this reaction step is carried out in an autoclave or in a par bomb, so that high pressures and temperatures can be reached. Pressure is generally freely increased, with an upper limit being that which the equipment can safely withstand, while temperature is preferably kept between 140°C and 200°C, even where relatively low temperatures can be used. As mentioned above, the overall yield of the process is always higher than 30% and often 50-70%, but the same 3,6
The yields of prior art processes starting from -dihalogenpyridazine derivatives range from 5% to 30%. The advantages of the invention are therefore obvious. Intermediates of the formula and have not been previously described in the chemical literature and are also an object of the present invention. The following examples illustrate the manner in which the invention may be practiced by one skilled in the art, but are not intended to limit the overall scope of the invention. Example 1 N-(2,5-dimethyl-1H-pyrrole-1-
yl)-6-(4-morpholinyl)-3-pyridazineamine A 3,6-dichloropyridazine (660 g, 4.4 mol), 98% hydrazine hydrate (226 g, 4.4 mol)
and sodium bicarbonate (375 g, 4.6 mol) in water (1800 ml) was heated to reflux temperature under stirring for 2 hours. Ethanol (100ml) was then slowly added and refluxing continued for a further 3 hours. Water (1000ml) was added and acetonylacetone (317g, 2.78mol) was added keeping the temperature above 60°C. The temperature rose and a pale yellow precipitate formed. suspension
The solution was neutralized with 17% hydrochloric acid, and the insoluble material collected after the filtration was washed with water until no chloro ions were present in the solution. The product is heated to 50℃ under reduced pressure.
Dry at 60°C. Yield 756g (93%), melting point 200°-202°C. The obtained 2,5-hexanedione-bis-(6-chloro-3-pyridazinyl)
-The structure of hydrazone was confirmed by IR and NMR spectra. B The product of the above reaction (587 g, 1.6 mol),
Acetic acid (500 ml) and acetonylacetone (183 g, 1.6 mol) were added slowly while heating to 90-110°C. Upon completion of the addition, a precipitate separated and the collected solid was washed with cold 50% aqueous acetic acid and dried under reduced pressure to yield 557 g (78%) of 6-chloro-
N-(2,5-dimethyl-1H-pyrrole-1-
yl)-3-pyridazineamine, melting point 173°~175
℃, was produced. C A mixture of the above product (89 g, 0.4 mol), morpholine hydrochloride (0.5 g, 0.005 mol) and morpholine (150 ml, 1.72 mol) was heated to reflux temperature for 3 hours. Water was added keeping the temperature above 85°C and the resulting suspension was stirred for 1 hour and then filtered. The collected insoluble material was washed with water and dried under reduced pressure to give 106 g.
of crude product was produced. from isopropanol
96 g (88%) of the title product was produced. Melting point: 190° to 192°C. The hydrochloride salt of the above product is described in Example 3 of European Patent Application Publication No. 9655. 6 in accordance with the method of application and British Patent No. 1157642
-Process starting from hydrazine-3-morpholino-pyridazine gives the title product of approx.
obtained in a yield of 25%, but in the method of the present invention starting from the same 3,6-dihalogenpyridazine.
The yield was 65%. Example 2 N-(2,5-dimethyl-1H-pyrrole-1-
yl)-6-(N,N-dimethylamino)-pyridazine, hydrochloride C 3-chloro-(2,5-dimethyl-1H-pyrrole obtained essentially according to sections A and B of Example 1) -1-yl)-pyridazine (40g, 0.18
mol), diethylamine hydrochloride (4 g) and diethylamine (92 g, 0.126 mol) in a par bomb with stirring at 160° to 160° for 14 hours.
When heated to 170℃, it reached 12 atmospheres. After distilling the solvent under reduced pressure, the residue was dissolved in boiling ethyl ether (200ml) and then hydrogen chloride was bubbled into the solution. The resulting precipitate was collected and dried to yield 44 g of the crude title product.
Crystallized with acetonitrile to give 27.2 g (51
%). Melting point: 168℃. While the prior art process according to European Patent Application Publication No. 9655 and Pihueri et al. (cited) gives the title product in 6% yield, the present process yields the same 3,
Starting from 6-dichloropyridazine derivative 36
gave a yield of %. Example 3 N-(2,5-dimethyl-1H-pyrrole-1-
yl)-N-methyl-6-(4-morpholinyl)
-3-Pyridazineamine A Water (300ml), 3,6-dichloropyridazine (29.8g, 0.2mol), Methylhydrazine (9.2g,
0.2 mol) and sodium bicarbonate (17.8 g,
0.2 mol) was heated to reflux temperature for 2 hours. After cooling to about 60° C., acetonylacetone (22.2 g, 0.2 mol) was added and stirring continued for an additional hour. The mixture was then neutralized with hydrochloric acid and the resulting precipitate was collected and crystallized from ethyl ether to give 28 g (59.2%)
6-chloro-N-(2,5-dimethyl-1H-
pyrrol-1-yl)-N-methyl-3-pyridazinamine, whose structure is IR and
Melting point 93° ~ confirmed by NMR spectrum
94.5℃. B The above product (10 g, 0.042 mol) was dissolved in morpholine (70 ml, 0.86 mol) and heated to reflux temperature for about 6 hours. The reaction mixture was then concentrated to dryness under reduced pressure, the residue was extracted with water and filtered. The collected solids were thoroughly washed and crystallized from a hexane/t-butyl ether mixture to give 10.5 g (82%) of the title product. Melting point: 119° to 122°C. The overall yield therefore amounts to about 40%, whereas the prior art methods (European Patent Application Publication No. 9655 and British Patent Application No. 1157642) give yields of about 13% starting from the same 3,6-dichloropyridazine. Example 4 Isolation of the intermediate 6-chloro-3-(methylhydrazine)-pyridazine A mixture of water, 3,6-dichloropyridazine, methylhydrazine and sodium bicarbonate was refluxed for 2 hours and then Cooled to room temperature. A solid was collected and identified as the title product. Melting point, 104°~106°C. The structure was confirmed by IR and NMR spectra.

Claims (1)

[Claims] 1. The following general formula [wherein R, R ¹ , R ² and R ³ may be the same or different and are independently selected from hydrogen and (C ₁ -C ₄ )alkyl, R ⁴ is hydrogen ,
(C ₁ -C ₄ )alkyl, mono- or di-(C _{1 -C 4} )
_C4 ) alkylamino-( _C1 - _C4 )alkyl, halo( _C1 - _C4 )alkanoyl, carbo( _C1 - _C4 )alkoxy, carbobenzyloxy; ^R5 and ^R6 are independently Hydrogen, ( _C1 - _C6 ) alkyl,
( _C3 - _C6 )alkenyl, ( _C3 - _C6 )alkynyl,
Hydroxy-( _C1 - _C6 )alkyl, ( _C1 - _C4 )alkoxy( _C1 - _C6 )alkyl, ( _C2 - _C6 )alkanoyloxy( _C1 - _C6 )alkyl, phenyl or phenyl( _C1 - _C4 )alkyl, where the phenyl group is independently chloro, bromo, fluoro, ( _C1 - _C4 )alkyl, ( _C1 - _C4 )alkoxy,
optionally substituted with 1 to 3 substituents selected from hydroxy and hydroxy( _C1 - _C4 )alkyl, or with methylenedioxy groups; or
R ⁵ and R ⁶ together with the adjacent nitrogen atoms represent a fully or partially hydrogenated 5- to 7-membered heterocyclic ring, which may contain other heterocyclic rings selected from O, N and S. ( _C1 - _C4 )alkyl, hydroxy, hydroxy ( _C1 - _C4 )alkyl, ( _C1 - _C4 )alkoxy, optionally substituted as above. may have one or two substituents selected from phenyl, R ⁷ and R ⁸ represent a hydrogen atom or together represent a 1,3-butadienylene group, which is pyridazine forming a benzo system condensed with a ring] and acid addition salts thereof; [wherein R ⁷ and R ⁸ have the meanings given above] is combined with a hydrazine hydrate or a suitable hydrazine derivative of the formula NH ₂ NH-R ⁴ [wherein R ⁴ has the meanings given above] , preferably in the presence of a hydrogen halide acceptor, to form the formula [wherein R ⁴ , R ⁷ and R ⁸ have the meanings given above] A 6-halogen-3-hydrazinopyridazine derivative of the formula [In the formula, R, R ¹ , R ² and R ³ have the above-mentioned meanings] by reacting with a dicarbonyl compound of the formula [In the formula, R, R ¹ , R ² , R ³ , R ⁴ , R ⁷ and R ⁸ have the above-mentioned meanings] to obtain an alkanedione-bis-[6-halo-3-pyridazinyl]-hydrazone, It is treated with equimolar amounts of the dicarbonyl compound described above, preferably in the presence of an acidic catalyst and a solvent, whereby the formula [wherein R, R ¹ , R ^{2 ,} R ³ , R ⁷ and R ⁸ have the above-mentioned meanings] A 6-halo-3-pyrrolylpyridazine amine derivative of formula A process characterized in that it is reacted with an amine of R ⁶ NH, in which R ⁵ and R ⁶ have the meanings given above, optionally in the presence of a suitable acidic catalyst. 2 R ¹ and R ² represent hydrogen, R and R ³ may be the same or different and represent (C ₁ -C ₄ ) alkyl, and R ⁵ and R ⁶ each independently ( _C1 - _C6 )alkyl, hydroxy( _C1 - _C6 )alkyl or ( _C1 - _C4 )alkoxy( _C1 - _C6 )alkyl, or ^R5 and ^R6
taken together with adjacent nitrogen atoms represents a 5- to 7-membered heterocyclic ring, which may contain other heteroatoms selected from O, N and S and (C ₁ -C ₄ ) alkyl, hydroxy, hydroxy( _C1 - _C4 )alkyl and optionally independently chloro,
1 or 2 selected from phenyl optionally having 1 to 3 substituents selected from fluoro, bromo, hydroxy( _C1 - _C4 )alkyl and ( _C1 - _C4 )alkoxy A method according to claim 1 for producing a compound of the formula which may have a substituent. 3. The reaction between the 3,6-dihalogenpyridazine and the hydrazine hydrate or hydrazine hydrate derivative is preferably carried out in an autoclave or parboil.
The method according to claim 1 or 2, which is carried out by heating to 100° to 190°C. 4 molar excess of dicarbonyl compound of formula 6
4. A process according to any one of claims 1 to 3, in which, in addition to the halogen-3-hydrazinopyridazine derivative, a derivative of the formula is directly obtained. 5 Alkanedione-bis-6-halogen-3-
A suitable solvent for the reaction of the pyridazine hydrazone with the dicarbonyl compound is selected from water, ( _C1 - _C4 ) alkanols, acetic or propionic acid, benzene, toluene, tetrahydrofuran, dioxane and mixtures thereof, and the acid catalyst is halogenated. 5. Process according to claims 1 to 4, selected from hydric acid, sulfuric acid, p-toluenesulfonic acid and Lewis acid. 6. Process according to any one of claims 1 to 5, characterized in that acetic acid is used both as solvent and as catalyst. 7. A process according to any one of claims 1 to 6, wherein the addition of the amine of the formula ^R5R6NH is carried out in the presence of an acid addition salt of ^the amine which acts as an acidic catalyst. 8 N-(2,5-dimethyl-1H-pyrrole-1
-yl)-6-(4-morpholinyl)-3-pyridazinamine Claim 1
7. The method according to any one of items 7 to 7. 9. A process according to claim 1, wherein the addition of the 6-halogen-3-hydrazinopyridazine derivative of the formula in about half a molar proportion of the dicarbonyl compound of the formula is carried out in an aqueous medium.